Intra- and inter-cellular signals that drive hepato-oncogenesis

驱动肝肿瘤发生的细胞内和细胞间信号

• 批准号: 10557925
• 负责人: Gen-Sheng Feng
• 金额: $ 41.38万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-10 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557925
• 关键词: Ablation; Animal Model; Automobile Driving; BAY 54-9085; Cells; Cessation of life; Chemicals; Clinical; Complement; Data; Diethylnitrosamine; Disease; Environment; Environmental Risk Factor; Epidermal Growth Factor Receptor; Excision; Goals; Hepatic; Hepatocarcinogenesis; Hepatocyte; Human; Immunotherapy; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Modeling; Molecular; Mus; NF-kappa B; Oncogenes; Oncogenic; Oncoproteins; Oxidative Stress; PIK3CA gene; Paper; Pathogenicity; Pathway interactions; Patients; Pharmacologic Substance; Pharmacy (field); Phenotype; Play; Primary carcinoma of the liver cells; Process; Proteins; Publishing; Research; Role; Sampling; Signal Pathway; Signal Transduction; Sister; TP53 gene; Testing; Therapeutic; Transfection; Tumor Promotion; Tumor Suppressor Proteins; beta catenin; cancer type; chemical carcinogen; design; experimental study; genetic analysis; interdisciplinary approach; kinase inhibitor; liver cancer model; liver cancer patient; liver inflammation; liver injury; mouse model; novel; novel therapeutic intervention; single-cell RNA sequencing; theories; therapeutically effective; tumor; tumorigenesis; tumorigenic

Liver cancer, mainly hepatocellular carcinoma (HCC), has become a most deadly malignant disease worldwide. So far, pharmaceutic inhibition of major oncogenic pathways has achieved little therapeutic benefit to liver cancer patients. We believe this is due to under- appreciation of the complexity in mechanisms of hepato-oncogenesis. In recent experiments, we and others have identified paradoxically anti-oncogenic effects of classical oncogenic molecules, such as c-Met, EGFR, β-catenin, Ikkβ, Jnk, and Shp2, in the liver. Ablating these molecules in hepatocytes enhanced HCC induced by chemical carcinogen DEN. To test a theory that loss of the oncogenic molecules generates an oncogenic microenvironment that promotes DEN-induced HCC, we have established another mouse HCC model, by transfection of oncogenic β-catenin (CAT), c-Met (MET) and PIK3CA (PIK), oncoproteins frequently detected in human HCCs. As expected, MET/CAT-driven HCC was aggravated in β-catenin-deficient liver, due to tumor-promoting factors induced by β-catenin removal. In contrast, Shp2 deletion dramatically suppressed HCC driven by MET/CAT or MET/PIK, despite a similar pro-tumorigenic environment in Shp2-deficient liver. Based on these novel unanticipated data, we propose a new hypothesis that although removal of Shp2 or β-catenin generates cell-extrinsic tumorigenic factors in the hepatic environment, the endogenous Shp2 is indispensable for oncogenic signaling in hepatocytes. To test this hypothesis, we propose three specific aims on this project. Aim 1 is to determine the cell-intrinsic role of Shp2 in hepato-oncogenic signaling. Aim 2 is to determine the cell-autonomous effect of β-catenin in liver tumorigenesis. Aim 3 is to search and identify cell-extrinsic factors induced by loss of the oncoproteins in hepatocytes. The results are expected to be instrumental for design of novel therapeutic strategies for liver cancer by inhibiting both cell-intrinsic oncogenic signals and the secondary environmental factors.

肝癌，主要是肝细胞癌(HCC)，已成为最致命的 世界范围内的恶性疾病。到目前为止，药物抑制主要致癌途径 对肝癌患者的治疗效果甚微。我们认为这是由于- 对肝脏肿瘤发生机制的复杂性的认识。在最近的实验中， 我们和其他人发现了经典致癌物质矛盾的抗致癌作用。 C-蛋氨酸、表皮生长因子受体、β-连环蛋白、IKKβ、jnk和shp2等分子在肝脏中的表达。烧蚀这些东西 肝细胞内分子对化学致癌物DEN诱导的肝细胞癌有促进作用。要测试一个 致癌分子的丢失会产生致癌微环境的理论 为了促进DEN诱导的肝癌，我们建立了另一种小鼠肝癌模型，通过 癌基因β-Catenin(CAT)、c-Met(Met)和PIK3CA(Pik)的转导 经常在人类碳氢化合物中检测到。正如预期的那样，MET/CAT驱动的肝细胞癌在 β-连环蛋白缺乏的肝脏，由于去除β-连环蛋白而诱导的促肿瘤因子。在……里面 相反，Shp2缺失可显著抑制MET/CAT或MET/PIK所致的肝细胞癌， 尽管在Shp2缺陷的肝脏中有类似的促肿瘤环境。基于这些小说 出乎意料的数据，我们提出了一个新的假设，尽管移除Shp2或β-连环蛋白 在肝脏环境中产生细胞-外源性致癌因子，内源性Shp2 对于肝细胞中的致癌信号来说是不可或缺的。为了检验这一假设，我们建议 这个项目的三个具体目标。目的1是确定Shp2在细胞中的内在作用。 肝脏致癌信号。目的2是确定β-连环蛋白的细胞自主效应。 肝脏肿瘤的发生。目标3是寻找和识别细胞外在因子，这些外在因子是由缺失的 肝细胞中的癌蛋白。研究结果可望对小说的设计有所帮助。 通过抑制细胞内源性致癌信号和联合治疗肝癌的策略 二次环境因素。